Identification of a cytokine-induced repressor of interleukin-1 stimulated expression of stromelysin 1 (MMP-3)
Identification of a cytokine-induced repressor of interleukin-1 stimulated expression of stromelysin 1 (MMP-3)
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DOI：
10.1074/jbc.274.4.2126
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Mochan, E
中科院分区：
文献类型：
--
作者：
Borghaei, RC;Sullivan, C;Mochan, E
Stromelysin 1 (MMP-3) 是一种具有广泛底物特异性的基质金属蛋白酶，与类风湿性关节炎和牙周炎等慢性炎症性疾病相关的关节和组织破坏有关。溶基质素基因的转录是由炎症细胞因子如白细胞介素 1 (IL-1) 和肿瘤坏死因子以及许多其他细胞因子和有丝分裂原诱导的，但其调节的确切机制尚不完全清楚。为了鉴定可能参与 IL-1 诱导溶基质素的转录因子和顺式元件，通过电泳迁移率变动分析筛选人滑膜和牙龈成纤维细胞中 IL-1 诱导的 DNA 结合复合物的人基质溶素 5' 侧翼区域。在这里，我们报告了这种与 -1614 至 -1595 区域 (5'-G(T)TTTTTCCCCCCATCAAAG-3') 结合的复合物的鉴定，称为基质溶素 IL-1 响应元件位点。肿瘤坏死因子也可诱导与该位点的结合，但血小板源性生长因子或白细胞介素 4 不会诱导该位点的结合。UV 交联表明至少有两种 DNA 结合蛋白参与其中，分别约为 48 和 52 kDa。人包皮成纤维细胞的瞬时转染实验表明，与该位点结合的蛋白质可抑制 IL-1 诱导的溶基质素基因的表达。
Stromelysin 1 (MMP-3) is a matrix metalloproteinase with broad substrate specificity that has been Linked to joint and tissue destruction associated with chronic inflammatory diseases such as rheumatoid arthritis and periodontitis. Transcription of the stromelysin gene is induced by inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor as well as a number of other cytokines and mitogens, but the exact mechanisms involved in its regulation are not fully understood. To identify transcription factors and cis elements potentially involved in the IL-1 induction of stromelysin, the human stromelysin 5'-flanking region was screened by electrophoretic mobility shift assay for IL-1-induced DNA-binding complexes in human synovial and gingival fibroblasts. Here we report the identification of such a complex binding to the region -1614 to -1595 (5'-G(T)TTTTTCCCCCCATCAAAG-3') termed the stromelysin IL-1 responsive element site. Binding to this site is also induced by tumor necrosis factor but not by platelet-derived growth factor or interleukin 4. UV cross-linking demonstrates that there are at least two DNA-binding proteins involved, of approximately 48 and 52 kDa. Transient transfection experiments in human foreskin fibroblasts demonstrate that proteins binding to this site act as a repressor of IL-1-induced expression of the stromelysin gene.